METTL3 stabilizes HDAC5 mRNA in an m6A-dependent manner to facilitate malignant proliferation of osteosarcoma cells

Renbing Jiang; Zhibing Dai; Junshen Wu; Suzhi Ji; Yachao Sun; Wenpeng Yang

doi:10.1038/s41420-022-00926-5

METTL3 stabilizes HDAC5 mRNA in an m⁶A-dependent manner to facilitate malignant proliferation of osteosarcoma cells

Cell Death Discov. 2022 Apr 8;8(1):179. doi: 10.1038/s41420-022-00926-5.

Authors

Renbing Jiang¹, Zhibing Dai², Junshen Wu², Suzhi Ji², Yachao Sun², Wenpeng Yang²

Affiliations

¹ Department of Bone and Soft Tissue, Affiliated Tumor Hospital of Xinjiang Medical University, 830011, Urumqi, Xinjiang, China. drjiangrenbing@163.com.
² Department of Bone and Soft Tissue, Affiliated Tumor Hospital of Xinjiang Medical University, 830011, Urumqi, Xinjiang, China.

Abstract

Osteosarcoma (OS) is a prevalent primary bone sarcoma. Methyltransferase-like 3 (METTL3) is dysregulated in human malignancies. This study explored the mechanism of METTL3 in OS cell proliferation. Our results demonstrated that METTL3 was highly expressed in OS, and correlated with the tumor size, clinical stage, and distant metastasis of OS patients. Higher METTL3 expression indicated poorer prognosis. METTL3 silencing inhibited the malignant proliferation of OS cells, while METTL3 overexpression led to an opposite trend. METTL3 upregulated histone deacetylase 5 (HDAC5) expression in OS cells by increasing the m⁶A level. HDAC5 reduced the enrichment of H3K9/K14ac on miR-142 promoter, thus suppressing miR-142-5p expression and upregulating armadillo-repeat-containing 8 (ARMC8) level. HDAC5 overexpression or miR-142-5p silencing attenuated the inhibitory effect of METTL3 silencing on OS cell proliferation. Xenograft tumor experiment in nude mice confirmed that METTL3 silencing repressed OS cell proliferation in vivo via the HDAC5/miR-142-5p/ARMC8 axis. Collectively, METTL3-mediated m⁶A modification facilitated OS cell proliferation via the HDAC5/miR-142-5p/ARMC8 axis.